Secretin is a naturally occurring, short-lived 27 amino acid neuropeptide hormone. Report of significant improvements in an autistic child treated with secretin has generated widespread clinical interest in its therapeutic potential since there is no FDA-approved treatment for autism. Studies in rodent have established that secretin transfers from blood into brain and can activate discrete brain regions. Synthetic human secretin analogs will be designed, using recently described strategies, to increase its stability and brain activity compared to the parent peptide. The secretin analogs generated in this Phase I will be tested in vitro for receptor binding and activation as well as in vivo for their ability to activate specific brain regions. Completion of these aims would validate the Phase II goal of developing a more active second generation secretin for the treatment of autism. In principle, the technologies developed to generate a more stable and active secretin could be applied to other therapeutic peptides.